619 Marfan syndrome (MFS) is an inherited connective tissue disorder, noteworthy for its worldwide distribution, relatively high prevalence, clinical variability, and pleiotropic manifesta- tions involving primarily the ocular, skeletal, and cardiovascu- lar systems, some of which are life threatening. Its estimated frequency is 2–3 per 10,000 individuals.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant
b. New mutation in about 25–30% of the cases
c. About 70–75% of individuals diagnosed with Marfan syndrome have an affected parent
2. Caused by a wide variety of mutations in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1
3. Molecular defects in the fibrillin gene are responsible for the impaired structural integrity of the skeletal, ocular, and cardiovascular systems
4. Almost all mutations are specific (unique) to a particular individual or family
5. FBN1 mutation is helpful diagnostically only if it has been previously found in the person who independently meets the criteria for Marfan syndrome
6. No obvious correlation between location of mutation and phenotypic severity (except an apparent clustering of muta- tions associated with the most severe form of Marfan syn- drome, i.e., neonatal Marfan syndrome)
7. Pathophysiological consequence of the elastic fiber degeneration: reduced distensibility in response to the pulse pressure wave or increased stiffness
8. Intrafamilial and interfamilial variability of clinical expression
9. Fibrillin-1 mutations also observed in related disorders of connective tissue (type I fibrillinopathies)
a. Autosomal dominant ectopia lentis (bilateral ectopia lentis without the typical skeletal and cardiovascular manifestations of the Marfan syndrome)
b. Shprintzen-Goldberg syndrome i. Marfanoid habitus ii. Craniosynostosis iii. Marfanoid habitus
iv. Mental retardation
v. Rarely aortic root dilatation vi. Mitral valve prolapse
c. Autosomal dominant Weill-Marchesani syndrome i. Ectopia lentis
ii. Short stature d. Ectopic lentis
i. Bilateral ectopia lentis ii. Scoliosis in some cases
iii. No cardiovascular manifestations
e. Familial aortic aneurysm
i. Ascending aortic aneurysm and dissection ii. No ectopia lentis
iii. No specific skeletal findings f. MASS phenotype
i. Mitral valve prolapse
ii. Aortic root dilation without dissection iii. Skeletal and skin abnormalities g. New variant of Marfan syndrome
i. Skeletal features of Marfan syndrome ii. Joint contractures
iii. Knee joint effusions iv. Ectopia lentis
v. No cardiovascular manifestations
h. Marfan-like (Marfanoid) skeletal abnormalities i. Tall stature
ii. Scoliosis
iii. Pectus excavatum iv. Arachnodactyly 10. The gene for fibrillin-2 (FBN2)
a. Mapped to chromosome 5q23-31 b. Highly homologous to FBN1
c. FBN2 mutations shown to cause a phenotypically related disorder called congenital contractural arachn- odactyly (Beals syndrome), which is characterized by:
i. Marfanoid habitus ii. Arachnodactyly iii. Camptodactyly
iv. Crumpled ears
v. Mild contractures of the elbows, knees, and hips vi. Mild muscle hypoplasia especially of the calf
muscles
CLINICAL FEATURES
Ghent criteria: For the diagnosis of Marfan syndrome in the first (index) case in a family, major criteria must be found in at least two different organ systems and minor criteria in a third body system. If a fibrillin-1 mutation is identified, a major criterion in one system and involvement of another sys- tem are required. In a relative of an individual with confirmed Marfan syndrome, a major criterion in one body system and involvement of another system is all that is needed for the diagnosis.
1. Skeletal system (requires at least 2 majors or 1 major plus 2 minors): affected patients are usually tall and thin with respect to the family profile. Limbs are disproportionate- ly long compared with the trunk (dolichostenomelia).
Arachnodactyly is a very common feature
a. Major criteria (requires at least four manifestations) i. Pectus carinatum
ii. Pectus excavatum requiring surgery
iii. Reduced upper-to-lower body segment ratio (<0.85 in Caucasians and <0.78 in African descents) or arm span-to-height ratio greater than 1.05. Arms and legs may be unusually long in proportion to the torso
iv. Positive wrist (Walker-Murdoch) and thumb (Steinberg) signs for arachnodactyly. Two sim- ple maneuvers may help demonstrate arachn- odactyly. First, the thumb sign is positive if the thumb, when completely opposed within the clenched hand, projects beyond the ulnar border.
Secondly, the wrist sign is positive if the distal phalanges of the first and fifth digits of one hand overlap when wrapped around the opposite wrist
v. Scoliosis ≥20° or spondylolisthesis. More than 60% of patients have scoliosis. Progression is more likely with curvature greater than 20° in growing patients
vi. Reduced extension of the elbows (<170°) vii. Medial displacement of the medial malleolus,
resulting in pes planus
viii. Protrusio acetabula (intrapelvic protrusion of the acetabulum; abnormally deep acetabulum with accelerated erosion) of any degree (ascertained by pelvic radiograph). Prevalence is about 50%
b. Minor criteria
i. Pectus excavatum of moderate severity ii. Joint hypermobility
iii. High arched palate with dental crowding iv. Typical face
a) Dolichocephaly b) Malar hypoplasia c) Enophthamos d) Retrognathia
e) Down-slanting palpebral fissures 2. Ocular system (requires 1 major or at least 2 minors)
a. Major criterion: ectopia lentis (usually superior temporal dislocation, almost always bilateral, occurs in up to 80% of affected individuals). This may present at birth or develop during childhood or adolescence
b. Minor criteria
i. Abnormally flat cornea (measured by keratometry) ii. Increased axial length of the globe (measured by
ultrasound)
iii. Hypoplastic iris or hypoplastic ciliary muscle causing decreased miosis
3. Cardiovascular system (requires one major or one minor):
the most serious problems associated with Marfan syn- drome
a. Major criteria
i. Dilatation of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva. The prevalence of aortic dilatation in Marfan syndrome is 70–80%. It presents at an early age, and tends to be more common in men than women
ii. Dissection involving the ascending aorta
b. Minor criteria
i. Mitral valve prolapse with or without mitral valve regurgitation. The prevalence of mitral valve prolapse is 55–69%
ii. Dilatation of main proximal pulmonary artery in the absence of valvular or peripheral pulmonic stenosis or any other obvious cause, below the age of 40 years
iii. Calcification of mitral annulus in patients less than 40 years of age
iv. Dilatation or dissection of abdominal or descend- ing thoracic aorta in patients less than 50 years of age
4. Pulmonary system (requires 1 minor) a. Major criterion: none
b. Minor criteria
i. Spontaneous pneumothorax: occurs in about 5%
of patients
ii. Apical blebs (on chest radiography) 5. Skin and integument (requires 1 minor)
a. Major criterion: none b. Minor criteria
i. Striae atrophicae (stretch marks) not associated with marked weight changes, pregnancy, or repetitive stress. Stretch marks are usually found on the shoulder, midback and thighs
ii. Recurrent or incisional hernia 6. Dura (requires the major)
a. Major criterion: lumbosacral ectasia (ballooning or widening of the dural sac) by CT or MRI. Fewer than 20% of patients experience serious dural ectasia.
Dural ectasia is thought to be caused by CSF pulsa- tions against weakened dura
b. Minor criteria: none
7. Family history (requires one major) a. Major criteria
i. Having a parent, child, or sibling who meets the diagnostic criteria independently
ii. Presence of a mutation in FBN1 known to cause the MFS
iii. Presence of a haplotype around FBN1, inherited by descent, known to be associated with unequivocally diagnosed MFS in the family b. Minor criterion: none
8. Other features not in the Ghent criteria a. Ocular features
i. Myopia (most common ocular feature)
ii. At increased risk for retinal detachment, glauco- ma, and early cataract formation
b. Skeletal system i. Bone overgrowth
ii. Disproportionately long extremities for the size of the trunk (dolichostenomelia)
iii. Overgrowth of the ribs pushing the sternum in (pectus excavatum) or out (pectus carina- tum)
iv. Mild, severe, or progressive scoliosis
9. Natural history: age-related nature of some clinical mani-
festations and variable phenotypic expression
a. At birth, early in life, and childhood i. Dolichostenomelia
ii. Arachnodactyly
iii. Manifestations of other organ systems usually not present at birth, making the diagnosis during neonatal period difficult in the absence of family history
iv. Asthenic habitus
v. Lens dislocation or lens subluxations (a hallmark feature) commonly diagnosed during the first year of life (not present at birth)
b. Childhood and puberty
i. Skeletal manifestations apparent during childhood ii. Pectus deformities and scoliosis worsen during
puberty
iii. Upper normal or larger than normal aortic root size in early childhood
iv. Rapidly increasing magnitude of dilatation dur- ing puberty
c. Adulthood
i. Lumbosacral dural ectasia manifesting as pro- gressive dilatation of the dura with consequent erosion of vertebral bone during adulthood ii. Aortic disease as the major cause of cardiovascu-
lar morbidity and reduced life expectancy (initial life expectancy: 32 ± 16 years)
iii. Increased life expectancy attributes to successive elective and emergent aortic surgery and to the use of beta-adrenergic receptor antagonists for the prevention of the progression of aortic root dilatation (current life expectancy; 41 ± 18 years) 10. Neonatal Marfan syndrome
a. Diagnosed early in life because of striking and severe clinical manifestations
i. Mitral or tricuspid insufficiency (multivalvular involvement)
ii. Congestive heart failure iii. Pulmonary emphysema
iv. Joint contractures
v. Death usually within the first year of life b. Characteristic aged facial appearance
i. Deep-set eyes
ii. Down-slanted palpebral fissures iii. Crumpled ears
iv. High arched palate
c. Striking arachnodactyly of the fingers and toes d. Pectus deformities
e. Scoliosis
f. Flexion contractures g. Pes planus
h. Aortic root dilatation i. Ectopia lentis
j. A cluster of mutations in exons 24–27 as well as in exons 31–32
DIAGNOSTIC INVESTIGATIONS
1. Annual physical examination including blood pressure measurement
2. Slit lamp examination for lens dislocation
3. Electrocardiogram for symptomatic palpitations, syncope or near-syncope, and conduction disturbance
4. Echocardiography and targeted imaging studies to care- fully monitor the cardiovascular status
a. Cross-sectional echocardiography for detecting aortic root dilatation
b. Standard echocardiography for assessing mitral valve prolapse, left ventricular size and function, left atrial size and tricuspid valve function
c. Transesophageal echocardiography for visualizing the distal ascending and descending aorta and assess- ing prosthetic valves
d. Doppler echocardiography for detecting and assess- ing the severity of aortic and mitral regurgitation 5. Radiography
a. Chest X-ray for apical blebs, enlargement of cardiac silhouette, and detecting dissecting aneurysm of aorta
b. Pelvic X-ray for additional diagnostic criteria of pro- trusio acetabulae
c. Feet X-ray for medial displacement of the medial malleolus, responsible for pes planus
6. Computed tomography (CT) and magnetic resonance imaging (MRI)
a. MRI best choice for assessing chronic dissection of any region of the aorta
b. CT or MRI of the lumbosacral spine for detecting dural ectasia
7. Aortograph: still considered by many to be the gold stan- dard for diagnosing acute aortic dissection, although sen- sitivity is not 100% and there are associated risks 8. Molecular analysis of FBN1 mutations
a. Routine mutation detection not available clinically due to the large size and complexity of FBN1 gene b. Mutations detected nearly always specific to each
family
c. FBN1 mutations observed in 20–80% of patients depending upon the clinical selection of patients and the mutation detection method used
d. Genotype–phenotype correlations
i. Little correlation observed in several hundred mutations reported to date
ii. Severe MFS detected in infancy (inappropriately termed neonatal MFS) usually caused by point mutations or small deletions in-frame in the epi- dermal growth factor (ECF)-like motifs in the middle third of the fibrillin-1 protein
iii. Less severe phenotype, verging on the MASS phenotype, usually caused by chain-terminating mutations resulting in essence in null mutants iv. Marked variability among individuals with the
same mutation
e. FBN1 mutations of various types reported i. Classic Marfan syndrome
ii. Nonclassical Marfan related phenotypes f. Molecular diagnosis practical in the following two
situations
i. Information about a known FBN1 mutation in a
person with MFS applied to relatives
ii. Linkage analysis using sufficient intragenic and tightly linked polymorphisms to MFS families with several available and willing relatives 9. Histology of the aorta
a. Elastic fiber fragmentation and disarray b. Paucity of smooth muscle cells
c. Deposition of collagen and the mucopolysaccharide between the cells of the media
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Recurrence risk: small if neither parent is affected ii. Gonadal mosaicism reported as the cause of multiple affected offspring being born to unaf- fected parents
iii. 50% if one parent is affected b. Patient’s offspring
i. 50% if the spouse is normal
ii. “Homozygous” MFS reported in case of an affected spouse
iii. “Compound heterozygosity” at the FBN1 locus confirmed at the molecular level; the affected child had a severe phenotype leading to early death 2. Prenatal diagnosis
a. Ultrasonography insensitive in the first two trimesters for detecting a fetus with MFS
b. Fetal echocardiography with careful limb length measurements by level II ultrasonography for at-risk pregnancy during 20th–24th weeks of gestation c. Molecular diagnosis
i. Only if the family’s mutation is known in an affected parent
ii. Presence of sufficient affected family members available for genetic linkage analysis if linkage with markers in and around the FBN1 locus can be established
d. Preimplantation diagnosis accomplished but compli- cated by the potential for selective PCR amplification of the normal allele as with all autosomal dominant conditions
3. Management
a. Address patients’ perceptions of Marfan syndrome and its associated pain, fatigue, and depressive symp- toms to enhance patient adaptation
b. Stress benefits about medication use ( β- or calcium- channel blockers to retard aortic root dilatation and dissection) and restriction of physical activities (to delay the onset of a severe cardiovascular event and prevent other syndrome-related problems such as lens dislocation)
i. β-blockers
a) Should be considered in all Marfan patients, particularly in the younger age group b) Not suitable for patients with asthma, car-
diac failure, or bradyarrhythmias
ii. Other treatments aimed at reducing the ejection impulse
a) Calcium antagonists
b) Angiotensin converting enzyme (ACE) inhibitors
c. Life style changes
i. Avoid competitive and collision/contact sports which are potentially dangerous due to under- lying aortic weakness and dilatation, valvular insufficiency, ocular abnormalities, and skeletal problems
ii. Avoid blows to the head such as boxing and high diving
iii. Protect against blows to the globe (racquet sports) with cushioned spectacles
iv. Avoid activities involving isometric work to pre- vent excessive elevations of systolic blood pres- sure and sudden death
a) Weight lifting
b) Climbing steep inclines c) Gymnastics
d) Water skiing e) Pull-ups
v. Avoid rapid decompression associated with quick ascents in elevators, scuba diving, and fly- ing in unpressurized aircraft to protect against pneumothorax
vi. Favor noncompetitive, isokinetic activity per- formed at a nonstrenous aerobic pace
a) Golfing b) Walking c) Fishing
d. Surgical intervention recommended for affected indi- viduals with significantly dilated or dissected aortic roots
e. Management of scoliosis i. Bracing
ii. Physical therapy
iii. Surgery for severe scoliosis f. Pectus repair
i. Repair of pectus excavatum to improve respira- tory mechanics: should be delayed until mid- adolescence to lessen the chance of recurrence ii. Repair of pectus carinatum performed mainly for
cosmetic purpose g. Pneumothorax
i. Chest tube: an appropriate initial therapy ii. Bleb resection and pleurodesis recommended
after one recurrence h. Ocular management
i. Removal of dislocated lens (pars plana Lensectomy and Vitrectomy), only in the follow- ing few instances, due to an increased risk of retinal detachment related to lens extraction a) Dislocation of a lens in the anterior chamber,
especially when it touches the corneal endothelium
b) Significant lens opacity
c) Evidence of lens-induced uveitis and glaucoma
d) Inadequate visual acuity that is not cor-
rectable by refraction and iris manipulation
e) Imminent complete luxation of the lens
ii. Lasers to restore a detached retina
i. Pregnancy in women with MFS
i. Preconceptional counseling of maternal risks during pregnancy and risk of transmitting the condition to offspring
ii. A significantly increased risk of cardiovascular complications during pregnancy, particularly risk of dissecting aortic aneurysm
iii. A high risk of spontaneous abortion but no other adverse maternal or fetal effects
iv. Need for close surveillance during pregnancy v. Avoid pregnancy if echocardiography suggests a
high risk of life-threatening cardiovascular com- promise. Pregnancy bears a 1% risk of fatal com- plication; the risk rises with increasing aortic root diameter.
vi. β-blockers recommended in pregnant women to prevent aortic dilatation
vii. Caesarean section should be offered at 38 weeks gestation if aortic root diameter is greater than 4.5 cm
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Fig. 2. Two Children with Marfan syndrome showing pectus and arachnodactyly. The first patient had dural ectasia detected by MRI.
The second patient had aortic root dilatation and mitral valve prolapse.
Fig. 3. A 4-year-old girl with Marfan syndrome showing pectus excurvatum and the operation scar from surgical correction of marked aortic dilatation. She also has hyperextensible joints and scoliosis.
Fig. 1. A boy with severe Marfan syndrome showing arachnodactyly, joint contractures, and aortic root dilatation, illustrated by the chest radiography.
Fig. 4. A 5-year-old boy with Marfan syndrome showing tall and slen- der body habitus. He was noted to have mitral valve prolapse and aor- tic root dilatation at age 2. In addition, he has bilateral lens disloca- tions and scoliosis.
Fig. 5. A child and an adult with Marfan syndrome showing high- arched palate.
Fig. 6. A child with Marfan syndrome showing cubitus valgus, arachnodactyly, post-surgical spinal fusion for severe scoliosis (illus- trated by radiograph).
Fig. 7. A boy with Marfan syndrome showing a slender/tall habitus and arachnodactyly.
Fig. 8. A girl with Marfan syndrome showing a slender/tall habitus, typical facies, arachnodactyly, and toe anomalies.
Fig. 10. Thumb and wrist signs.
Fig. 9. Arachnodactyly in two adult patients with Marfan syndrome.
Fig. 11. Hypermobile joints in two patients with Marfan syndrome.
Fig. 12. Stretch marks in the shoulders in one patient and in the but- tock region in other patient with Marfan syndrome.
Fig. 13. Familial Marfan syndrome in a mother and a son showing extreme myopia (lens dislocation) and thumb and wrist signs.
Fig. 14. MRI of the lumbosacral spine in two patients showing dural ectasia.
Fig. 15. A 20-year-old male with Marfan syndrome with repeat spon- taneous pneumothorax from ruptures of apical blebs. The chest X-ray shows collapsed left lung with pleural line (arrows). The CT of the chest shows pneumothorax on the right lung (arrows). Thoracoscope image from the right lung shows two bands representing the old adhe- sions due to previously ruptured apical blebs (black arrows) and two intact blebs (white arrows). The wedge biopsy specimen of the right apex shows two emphysematous blebs (white arrows) which were demonstrated in the previous figure.
